Leukotriene A.sub.4 (hereinafter abbreviated as LTA.sub.4) hydrolase, which is one of epoxide hydrolases, is a metal-containing enzyme which requires zinc in its active center.
LTA.sub.4 hydrolase plays a catalyst-like role on biochemical conversion from LTA.sub.4 into leukotriene B.sub.4 (hereinafter abbreviated as LTB.sub.4), which is a strong pro-inflammatory substance.
LTB.sub.4 is an arachidonic acid metabolite which is produced in 5-lipoxygenase pathway, is biosynthesized in various cells including mast cell, neutrophil, monocyte, macrophage, etc., and plays a role as an important mediator in inflammation. LTB.sub.4 induces chemotaxis, aggregation and degranulation of leukocyte and accumulation of polymorphonuclear leukocyte, and accelerates blood-vessel permeability and edema formation. For this reason, it was reported that particularly high level of LTB.sub.4 is detected at lesion sites in inflammatory diseases such as rheumatic diseases (J. Clin. Invest., 66, 1166-1170 (1980)), psoriasis (Br. J. Pharmacol., 83, 313-317 (1984)), inflammatory bowel diseases (Gastroenterology, 86, 453-460 (1984)) and gout (Lancet, 2, 1122-1124 (1982)), and in sputum in cystic fibrosis (Lancet, 342, 465-469 (1993)).
Accordingly, compounds which inhibit LTA.sub.4 hydrolase are expected to prevent production of LTB.sub.4 and exhibit therapeutic effects on inflammatory diseases such as rheumatic diseases.
Mercaptoacylproline derivatives, which are active ingredients in the present invention, are reported in U.S. Pat. No. 4,316,906 and J. Med. Chem., 31, 875-885 (1988) as antihypertensive agents having inhibitory effects on ACE. However, there is no report about LTA.sub.4 hydrolase inhibition effects of compounds having a substituent in 4th-position of proline skeleton of these mercaptoacylproline derivatives. Compounds having a (lower cycloalkylphenyl)alkyl group in 4th-position of proline skeleton are novel compounds which are not described in literature.
As mentioned above, the mercaptoacylproline derivatives are known to have the inhibitory effects on ACE and to be useful as the antihypertensive agents. However, it is a very interesting subject to find new medical use of these compounds.
The present inventors studied in order to find new medical use of the known mercaptoacylproline derivatives and mercaptoacylproline derivatives synthesized newly. As a result, these compounds were found to exhibit excellent inhibitory activities on LTA.sub.4 hydrolase.